Multi-lineage differentiation of mesenchymal stem cells – To Wnt,or not Wnt

Mesenchymal stem cells (MSCs) are multipotent precursor cells originating from several adult connective tissues. MSCs possess the ability to self-renew and differentiate into several lineages, and are recognized by the expression of unique cell surface markers. Several lines of evidence suggest that various signal transduction pathways and their interplay regulate MSC differentiation. To that end, a critical player in regulating MSC differentiation is a group of proteins encoded by the Wnt gene family, which was previously known for influencing various stages of embryonic development and cell fate determination. As MSCs have gained significant clinical attention for their potential applications in regenerative medicine, it is imperative to unravel the mechanisms by which molecular regulators control differentiation of MSCs for designing cell-based therapeutics. It is rather coincidental that the functional outcome(s) of Wnt-induced signals share similarities with cellular redox-mediated networks from the standpoint of MSC biology. Furthermore, there is evidence for a crosstalk between Wnt and redox signalling, which begs the question whether Wnt-mediated differentiation signals involve the intermediary role of reactive oxygen species. In this review, we summarize the impact of Wnt signalling on multi-lineage differentiation of MSCs, and attempt to unravel the intricate interplay between Wnt and redox signals.     

Wnt基因/Wnt信号通路与乳腺癌

Wnt蛋白是一组调控胚胎形成期间细胞间信号传导的高度保守的分泌信号分子.在过去的几年里,由Wnt蛋白触发的不同信号通路已经得到了详尽的研究.Wnt基因与Wnt信号通路组成分子的突变可引起发育缺陷,异常的Wnt信号传导可导致人类疾病包括肿瘤的发生.许多证据都表明,Wnt信号通路的失调与乳腺癌的发生发展密切相关.micro...     

BMP, Wnt and Hedgehog signals: how far can they go?

Wnt, Hedgehog and bone morphogenetic proteins function as either short-range or long-range signaling molecules depending on the tissue in which they are expressed. In the past year, filapodia-like cytoplasmic extensions, cell-surface proteogylcans and/or extracellular binding proteins have been identified that may enable these molecules to signal at a distance. Furthermore, recent studies suggest that variations in the signaling range of these molecules may be due to tissue-specific differences in intracellular processing or tissue-restricted expression of binding proteins.     

The what,where, when and how of Wnt/β-catenin signaling in pancreas development

The Wnt/β-catenin signaling pathway, conserved across the animal kingdom, is critical for the development of numerous tissues. Several recent studies have focused on the roles that this pathway plays at different stages of pancreatic organogenesis, including specification, proliferation, differentiation and function. Whereas, during early endoderm development, inhibition of the pathway is required for pancreatic specification, subsequent growth and differentiation of the fetal organ depends on the pathway being active. This appears especially true for exocrine acinar cells, the specification and differentiation of which also depend on β-catenin function. Whether the pathway plays an important role in development or function of endocrine islet cells, including insulin-producing β-cells, remains controversial. This question is particularly important in light of recent studies that implicate a downstream component of the pathway, TCF7L2, in human β-cell function. This review will cover recent work on Wnt/β-catenin signaling in pancreas development, emphasizing those points of controversy that most urgently require further investigation.     

Wnt基因族的进化

Ｗｎｔ基因族的进化马德如（南开大学分子生物学研究所,天津３０００７１）关键词Ｗｎｔ基因,分子进化一八十年代以来大量证据表明,原癌基因（ｐｒｏｔｏｏｎｃｏｇｅｎｅｓ）在细胞分化和胚胎发育中有重要作用。其中突出的例证是１９８２年由Ｎｕｓｓｅ和Ｖａｒｍｕｓ...     

Modeling oscillatory control in NF-κB, p53 and Wnt signaling

Oscillations are commonly observed in cellular behavior and span a wide range of timescales, from seconds in calcium signaling to 24 hours in circadian rhythms. In between lie oscillations with time periods of 1-5 hours seen in NF-κB, p53 and Wnt signaling, which play key roles in the immune system, cell growth/death and embryo development, respectively. In the first part of this article, we provide a brief overview of simple deterministic models of oscillations. In particular, we explain the mechanism of saturated degradation that has been used to model oscillations in the NF-κB, p53 and Wnt systems. The second part deals with the potential physiological role of oscillations. We use the simple models described earlier to explore whether oscillatory signals can encode more information than steady-state signals. We then discuss a few simple genetic circuits that could decode information stored in the average, amplitude or frequency of oscillations. The presence of frequency-detector circuit downstream of NF-κB or p53 would be a strong clue that oscillations are important for the physiological response of these signaling systems.     

The what, where, when and how of Wnt/β-catenin signaling in pancreas development

The Wnt/β-catenin signaling pathway, conserved across the animal kingdom, is critical for the development of numerous tissues. Several recent studies have focused on the roles that this pathway plays at different stages of pancreatic organogenesis, including specification, proliferation, differentiation and function. Whereas, during early endoderm development, inhibition of the pathway is required for pancreatic specification, subsequent growth and differentiation of the fetal organ depends on the pathway being active. This appears especially true for exocrine acinar cells, the specification and differentiation of which also depend on β-catenin function. Whether the pathway plays an important role in development or function of endocrine islet cells, including insulin-producing β-cells, remains controversial. This question is particularly important in light of recent studies that implicate a downstream component of the pathway, TCF7L2, in human β-cell function. This review will cover recent work on Wnt/β-catenin signaling in pancreas development, emphasizing those points of controversy that most urgently require further investigation.     

Wnt信号转导及其生物效应

 Wnt蛋白与其下游效应物构成一组重要的信号转导通路 .信号转导过程包括 :Wnt首先激活细胞表面受体佛力子 (FZ) ,活化的FZ将通过Dvl、CKIε抑制糖原合成酶激酶 3β ,继而拮抗 β 链结素( β cat)催毁器的作用 ,使胞浆中 β cat积聚并进入核内 .β cat在核内与转录因子LEF TCF协作 ,激活控制胚胎发育和细胞命运的靶基因 ;活化的FZ还经激活JNK及Flamingo来影响细胞骨架的聚合 ,以决定细胞的平面极性及纺缍体定位     

Wnt5a抑制Wnt3a促黑素细胞黑素生成的作用探究

目的：研究WntSa对Wnt3a处理过的melan—a细胞分泌黑色素的影响。方法：体外培养黑色素细胞（melan-a细胞）,分别进行GFP、Wnt3a、Wnt3a＋WntSa处理,比较细胞的突起,酪氨酸酶的活性以及黑素合成相关基因（TYR、TRP2、MITF）表达情况。结果：Wnt3a促进黑色素细胞突起的生长和TYR、TRP2、MITF的表达,而Wnt5a逆转了Wnt3a对黑色素细胞的作用。结论：Wnt5a抑制Wnt3a促黑素细胞黑素生成的作用,表明在melan．a黑素细胞中Wnt5a可有效抑制wnt经典通路。     

Discovery of Klotho peptide antagonists against Wnt3 and Wnt3a target proteins using combination of protein engineering,protein–protein docking,peptide docking and molecular dynamics simulations

The Klotho is known as lifespan enhancing protein involved in antagonizing the effect of Wnt proteins. Wnt proteins are stem cell regulators, and uninterrupted exposure of Wnt proteins to the cell can cause stem and progenitor cell senescence, which may lead to aging. Keeping in mind the importance of Klotho in Wnt signaling, in silico approaches have been applied to study the important interactions between Klotho and Wnt3 and Wnt3a (wingless-type mouse mammary tumor virus (MMTV) integration site family members 3 and 3a). The main aim of the study is to identify important residues of the Klotho that help in designing peptides which can act as Wnt antagonists. For this aim, a protein engineering study is performed for Klotho, Wnt3 and Wnt3a. During the theoretical analysis of homology models, unexpected role of number of disulfide bonds and secondary structure elements has been witnessed in case of Wnt3 and Wnt3a proteins. Different in silico experiments were carried out to observe the effect of correct number of disulfide bonds on 3D protein models. For this aim, total of 10 molecular dynamics (MD) simulations were carried out for each system. Based on the protein–protein docking simulations of selected protein models of Klotho with Wnt3 and Wnt3a, different peptides derived from Klotho have been designed. Wnt3 and Wnt3a proteins have three important domains: Index finger, N-terminal domain and a patch of ～10 residues on the solvent exposed surface of palm domain. Protein–peptide docking of designed peptides of Klotho against three important domains of palmitoylated Wnt3 and Wnt3a yields encouraging results and leads better understanding of the Wnt protein inhibition by proposed Klotho peptides. Further in vitro studies can be carried out to verify effects of novel designed peptides as Wnt antagonists.     

Wnt基因的类别及功能

Wnt是一类癌基因,在动物发育过程中具有广泛的作用。该文介绍哺乳动物基因组中19个Wnt基因的功能。     

Wnt信号通路与神经干细胞

神经干细胞增殖、分化机制的研究为神经系统疾病治疗提供了新的途径,具有巨大的潜在应用价值和理论研究意义。业已发现,Wnt信号通路对神经干细胞的增殖发挥着决定性作用,但新近的研究却表明Wnt信号能够明显促进神经干细胞向神经元分化,这种不同的表现可能与神经干细胞的内在特点、周围环境及靶基因的不同有关。本文试从Wnt信号通路及其在调控神经干细胞的增殖、分化中的作用加以综述。     

Maternal xNorrin, a canonical Wnt signaling agonist and TGF-β antagonist, controls early neuroectoderm specification in Xenopus

Dorsal-ventral specification in the amphibian embryo is controlled by β-catenin, whose activation in all dorsal cells is dependent on maternal Wnt11. However, it remains unknown whether other maternally secreted factors contribute to β-catenin activation in the dorsal ectoderm. Here, we show that maternal Xenopus Norrin (xNorrin) promotes anterior neural tissue formation in ventralized embryos. Conversely, when xNorrin function is inhibited, early canonical Wnt signaling in the dorsal ectoderm and the early expression of the zygotic neural inducers Chordin, Noggin, and Xnr3 are severely suppressed, causing the loss of anterior structures. In addition, xNorrin potently inhibits BMP- and Nodal/Activin-related functions through direct binding to the ligands. Moreover, a subset of Norrin mutants identified in humans with Norrie disease retain Wnt activation but show defective inhibition of Nodal/Activin-related signaling in mesoderm induction, suggesting that this disinhibition causes Norrie disease. Thus, xNorrin is an unusual molecule that acts on two major signaling pathways, Wnt and TGF-β, in opposite ways and is essential for early neuroectoderm specification.     

Wnt信号通路与哺乳动物生殖

Wnt蛋白及其受体、调节蛋白等一起组成了复杂的信号通路,调控细胞的分化,参与发育的多个重要过程.近来的研究表明：Wnt信号通路也是调节哺乳动物生殖系统正常发育所必需.它主要参与了缪勒氏管及其派生器官的形成,调控卵泡的发育、排卵及黄体化,另外与正常妊娠的建立以及妊娠过程中乳腺的变化也有关.     

谷氨酰胺合成酶与Wnt信号转导通路

GS（glutamine synthetase）或GLuL（glutamate-ammonia ligase）,即谷氨酰胺合成酶,为人体内重要的功能酶,催化谷氨酸与氨生成谷氨酰胺。在体内氮的代谢中,尤其在维持氨离子和谷氨酰胺的稳定中发挥着重要的作用。GS表达和活性的异常常会导致人体很多疾病的发生。近年来研究发现GS表达和活性的异常与Wnt信号通路的异常密切相关。     

LGR5 interacts and cointernalizes with Wnt receptors to modulate Wnt/β-catenin signaling

LGR5, a seven-transmembrane domain receptor of the rhodopsin family, is a Wnt target gene and a bona fide marker of adult stem cells in the gastrointestinal tract and hair follicle bulge. Recently, we and others demonstrated that LGR5 and its homologues function as receptors of the R-spondin family of stem cell factors to potentiate Wnt/β-catenin signaling. However, the mechanism of how LGR5 enhances the signaling output remains unclear. Here we report that following costimulation with the ligands R-spondin1 and Wnt3a, LGR5 interacts and forms a supercomplex with the Wnt coreceptors LRP6 and Fzd5 which is rapidly internalized and then degraded. Internalization of LGR5 is mediated through a dynamin- and clathrin-dependent pathway. Inhibition of this endocytic process has no effect on LGR5 signaling. Deletion of the C-terminal tail of LGR5 maintains its ability to interact with LRP6, yet this LGR5 mutant exhibits increased signaling activity and a decreased rate of endocytosis in response to R-spondin1 compared to the wild-type receptor. This study provides direct evidence that LGR5 becomes part of the Wnt signaling complex at the membrane level to enhance Wnt/β-catenin signaling. However, internalization of LGR5 does not appear to be essential for potentiating the canonical Wnt signaling pathway.